'Caloric restriction works by rejuvenating the biological clock in a most powerful way

While most of us are probably familiar with the concept of the circadian body clock, which dictates our rhythms of sleep or wakefulness, a relatively new concept known as the epigenetic clock could inform us about how swiftly our bodies age, and how prone we are to diseases of old age. Scientists at the University of Exeter have now developed a new epigenetic clock specifically for the human brain. Developed using human brain tissue samples, the new model is claimed to be far more accurate for the human brain than previous versions that were based on blood samples or other tissues. The researchers hope that it will provide new insights into how accelerated aging in the brain could be associated with brain disorders such as Alzheimer’s disease and other forms of dementia.

Research lead Jonathan Mill, PhD, commented, “The research area of epigenetic clocks is a really exciting, and has the potential to help us understand the mechanisms involved in aging. Our new clock will help us explore accelerated aging in the human brain.”

Mill and colleagues report on their developments in Brain, in a paper titled, “Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex.”

People age at different rates, with some individuals developing both characteristics and diseases related to aging earlier in life than others. Learning more about this ‘biological age’ could help us understand more about how we can prevent age-related diseases, such as dementia. “Because of substantial inter-individual variation in age-associated phenotypes, there is considerable interest in identifying robust biomarkers of ‘biological’ age, a quantitative phenotype that is thought to better capture an individual’s risk of age-related outcomes than actual chronological age,” the authors wrote. Understanding the biological mechanisms involved in aging processes will be critical for scientists to work towards preventing, slowing or even reversing age-associated phenotypes.

Epigenetic mechanisms control the extent to which genes are switched on and off across the different cell-types and tissues that make up a human body. Unlike our genetic code, these epigenetic marks change over time, and these changes can be used to accurately predict biological age from a DNA sample. “There has been recent interest in the dynamic changes in epigenetic processes over the life course, and a number of ‘epigenetic clocks’ based on one specific epigenetic modification, DNA methylation (DNAm), have been developed that appear to be highly predictive of chronological age.” Previous clocks have typically been based samples of, say, blood, and from people in mid-life, but the authors point out such clocks might not be accurate when applied to other tissues. “Importantly, although these DNAm age estimators have increased predictive accuracy within the specific tissues in which they were built, they lose this precision when applied to other tissues.”

To develop their epigenetic clock the University of Exeter researchers took the unique approach of analyzing DNA methylation in 1,397 samples of human brain cortex—a region of the brain that is involved in cognition, and implicated in diseases such as Alzheimer’s disease—from people aged between one and 108 years.

Their studies identified 347 DNA methylation sites that, when analyzed in combination, appeared to optimally predict age in the human cortex. They then tested their model in a separate collection of 1,221 human brain samples from the Brains for Dementia Research (BDR) cohort, which is funded by the Alzheimer’s Society and Alzheimer’s Research UK, and in a dataset of 1,175 blood samples.

The results led the team to conclude that their clock “was far more accurate than existing DNAm-based predictors developed for other tissues.” The wide age range was another strength that makes the new model a more accurate predictor. “… we show that previous epigenetic clocks systematically underestimate age in older samples and do not perform as well in human cortex tissue,” they noted. “Our findings suggest that previous associations between predicted DNAm age and neurodegenerative phenotypes may represent false positives resulting from suboptimal calibration of DNAm clocks for the tissue being tested and for phenotypes that manifest at older ages.” The investigators further stressed the importance of considering age distribution and the tissue type of samples in the training datasets when developing and using epigenetic clock models to analyze human epidemiological or disease cohorts.

First author Gemma Shireby, who carried out the research as part of her PhD at the University of Exeter, said: “Our new epigenetic body clock dramatically outperformed previous models in predicting biological age in the human brain. Our study highlights the importance of using tissue that is relevant to the mechanism you want to explore when developing epigenetic clock models. In this case, using brain tissue ensures the epigenetic clock is properly calibrated to investigate dementia.”

Mill added, “As we’re using brain samples, this clearly isn’t a model that can be used in living people to tell how fast they’ll age—however, we can apply it to donated brain tissue to help us learn more about the factors involved in brain diseases such as dementia.”

The research team is now working on using the model on brain samples of people who had Alzheimer’s disease. They hypothesize that they will find evidence for elevated biological aging in these samples. Fiona Carragher, Director of Research and Influencing at Alzheimer’s Society, which funded the newly reported work, said, “Epigenetics is a flourishing area of dementia research and this study is extremely valuable as we continue to better understand the role and impact of Alzheimer’s disease in brain aging. If we can more accurately predict aging of the brain and unpick the underlying causes of this highly complex condition, we have the greatest opportunity to develop effective treatments that could slow its progression.”

“This work is only possible because of support from charities like Alzheimer’s Society, which funded this work, but we need more investment. The Government must commit to doubling dementia research funding so we can keep momentum in this field, giving hope to the 850,000 people living with dementia in the U.K. today.”

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